This invention relates to pharmaceutical compositions for transdermal administration of prostaglandin drugs to a patient.
Prostaglandin E1 is a derivative of prostanoic acid, a 20-carbon atom lipid acid, represented by the formula: 
and is commercially available, e.g., from Chinoin Pharmaceutical and Chemical Works Ltd. (Budapest, Hungary) under the designation xe2x80x9cAlprostadil USPxe2x80x9d and from The Upjohn Company (Kalamazoo, Mich.) under the designation xe2x80x9cProstin VR.xe2x80x9d
Prostaglandin E1 is a vasodilator useful to maintain open blood vessels and therefore, to treat peripheral vascular disease among other ailments. While the potential benefits from transdermal delivery of prostaglandin E1 have long been recognized, prior efforts at developing a topical composition for prostaglandin delivery have not been fully successful.
In particular, there is presently no commercial source for a topical semi-solid formulation that is useful without a supporting device such as a patch, adhesive strip, and the like. For example, U.S. Pat. No. 5,380,760 to Wendel et al. is directed to a topical prostaglandin formulation that includes a pressure-sensitive, adhesive sheet of polyisobutylene.
Working alone most drugs, prostaglandin formulations included, do not sufficiently permeate the skin to provide drug concentration levels comparable to those obtained from other drug delivery routes. To overcome this problem, topical drug formulations typically include a skin penetration enhancer. Skin penetration enhancers also may be referred to as absorption enhancers, accelerants, adjuvants, solubilizers, sorption promoters, etc. Whatever the name, such agents serve to improve drug absorption across the skin. Ideal penetration enhancers not only increase drug flux across the skin, but do so without irritating, sensitizing, or damaging skin. Furthermore, ideal penetration enhancers should not affect available dosage forms (e.g. cream or gel), or cosmetic quality of the topical composition.
A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the use and testing of various skin penetration enhancers, and Bxc3xcyxc3xcktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997).
A fully successful formulation for prostaglandin E1 has not yet been identified. Unfortunately, prostaglandin E1 is readily transformed by rearrangement and other reactions. This relative instability tends to complicate efforts at formulating composition for transdermal delivery.
The present invention addresses these problems by providing a semi-solid, separation resistant composition for relatively rapid, sustained delivery of prostaglandin E1.
A pharmaceutical composition suitable for topical application comprises prostaglandin E1, a penetration enhancer, a polysaccharide gum, a lipophilic compound, and an acidic buffer system. The penetration enhancer can be an alkyl-2-(substituted amino)-alkanoate ester, a (substituted amino)-alkanol alkanoate, a mixture of these, or an acid addition salt thereof. The acid can be organic or inorganic. The lipophilic compound may be an aliphatic C1 to C8 alcohol, an aliphatic C8 to C30 ester, or a mixture of these. The composition includes a buffer system capable of providing a buffered pH value for said composition in the range of about 3 to about 7.4. If desired, stabilizers and emulsifiers may be included.
Compositions of the present invention can take the form of a semi-solid suitable for topical application. In use as a topical agent, these compositions exhibit relatively high prostaglandin penetration and bioavailability without requiring a wasteful overloading prostaglandin concentration. The compositions further exhibit reduced skin irritation, sensitivity and damage.
Other and further aims, purposes, features, advantages, embodiments and the like will be apparent to those skilled in the art from the present specification and the appended claims.